Cancer cells are characterized by multiple genetic alterations that confer physiological changes, leading to uncontrolled division and ability to invade other tissues. These acquired capabilities, namely self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis are essential for malignant growth. Recent studies have associated the family of enzymes known as the proprotein convertases (PCs) to cancer (Bassi et al., 2005, Mol. Carcinog., 44: 151-161; Khatib et al., 2002, Am. J. Pathol., 160: 1921-1935). PCs are serine proteases that optimally cleave substrates at R—X—K/R—R motif. These processing events, resulting in the activation of protein precursors, occur at multiple levels of cell secretory pathways, and even at the cell surface.
In mammalian cells, seven members of this family have been identified: furin, PACE4, PC1/3, PC2, PC4, PC5/6 and PC7, with differential expression in tissues, ranging from ubiquitous (eg. furin) to an endocrine restricted expression (PC1/3 and PC2).
The association of PCs with cancer was firstly done by comparative studies of normal and cancerous cells showing higher expression of PCs in small cell lung cancer (Clark et al., 1993, Peptides, 14: 1021-1028), non-small cell lung carcinoma (Mbikay et al., 1997, Cancer, 75: 1509-1514), breast (Cheng et al., 1997, Int. J. Cancer, 71: 966-971), colon (Tzimas et al., 2005, BMC Cancer, 5: 149), and head and neck (Bassi et al., Mol. Carcinog., 31: 224-232) tumors cells. A correlation between expression of some PCs, namely furin and PACE4, and tumor cell aggressiveness has been established for different cell types. It as been demonstrated that the overexpression of PACE4 in non-malignant keratinocyte cell lines renders these cells malignant. Non-selective inhibitors that target several PCs together (such as furin, PACE4 and PC5/6 together) have been described (Bassi et al., 2005, Cancer Res., 65: 7310-7319; Mahloogi et al., 2002, Carcinogenesis, 23: 565-572; Bassi et al., 2000, Mol. Carcinog., 28: 63-69; Hubbard et al., 1997, Cancer Res., 57: 5226-5231).
Moreover, it has been proposed that PC activity regulates epithelial cell differentiation in a prostate cancer cell line. One possible mechanism underlying these observations could be on the basis of the precursors activation by overexpressed PCs. Thus, it is hypothesized that aberrant processing events provide cancer cells a higher capacity to (i) remodel the extracellular; (ii) to interact with their host micro-environment to favor tumor cell adhesion and; (iii) to modulate their proliferation and differentiation. Alternatively, PC's overexpression is required to sustain these pathophysiological functions to maintain cancer cells immortality
The situation becomes more complex as the expression/activity of PCs are modulated differently in various cancer cells or cancer models. If one wishes to understand the specific contribution of each PC in tumorigenesis, the necessity for potent, specific and cell effective inhibitors, either pharmacologic or molecular, for each member of this enzyme family is crucial. Until now, these pharmacological tools are limited and lack specificity for single PCs.
It would be highly desirable to be provided with selective PCs inhibitors. It would also be highly desirable to be provided with selective PCs inhibitors that are effective in treating cancer. More specifically, it would be highly desirable to be provided with selective PCs inhibitors that have antiproliferative effects.